Endometrial cancer is the most common gynecologic malignancy in the United States. Approximately 39,800 new cases of cancer of the uterine corpus will be diagnosed and 7,400 women will die of this disease in 2007. The incidence in the United States is among the highest in the world. Fortunately, most women present with early stage disease and surgery alone (hysterectomy) is curative. The overall five-year survival rate for endometrial cancer patients is estimated at 80-85%. Despite the high cure rate, endometrial cancer remains a clinically challenging disease. Adjuvant therapies (radiation, hormonal, chemotherapy, or combinations) for women with advanced stage, progressive or recurrent disease are not very effective at this time. The median survival after recurrence is ten months and the five-year survival for patients who have recurred is <15%. Effective treatments for advanced and recurrent endometrial carcinoma remain to be defined. New biologic or targeted therapies based on an understanding of the underlying causes of disease hold promise for better outcomes for women with endometrial cancer. We recently determined activating mutations in the FGFR2 oncogene are present in approximately 15% of endometrioid endometrial cancers. Anti-FGFR therapeutics are already in clinical trails for other malignancies and may prove useful in the treatment of endometrial cancers. We propose to analyze endometrial cancers from the Gynecologic Oncology Group Protocol 210 to better understand the clinical significance of FGFR2 mutations and the relationship between activation of FGFR2 and loss of DNA mismatch repair, a key early event in the initiation of ~30% of endometrioid endometrial cancers. Two specific aims are proposed: Specific Aim 1: Determine the role FGFR2 mutations play in intermediate and high risk endometrial cancers. We will assess the rate and spectrum of mutations by direct sequencing and test targeted mutation detection in ~550 endometrioid cancer specimens from GOG-210. We will determine the relationship between FGFR2 mutation and clinicopathologic variables including disease-free and overall survival. Specific Aim 2: Determine the relationship between loss of DNA mismatch repair and FGFR2 mutation. Our preliminary studies suggest FGFR2 mutation may be more common in tumors lacking DNA mismatch repair. Understanding what pathways are dysregulated in cancers will be critical to developing biologic therapies. Understanding of the clinical significance of FGFR2 mutations in endometrial cancer is a critical first step towards determining whether FGFR inhibitors could be useful in treating patients with endometrial cancer. PUBLIC HEALTH RELEVANCE: Our collaborative group recently determined activating mutations in the fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinase gene are frequent in uterine endometrial cancers. The FGFR2 gene product is a potential therapeutic target, with several biologics with activity against FGFR2 already in clinical trials. In this proposal we will evaluate endometrial cancers from the NCI-funded Gynecologic Oncology Group Protocol 210 "A molecular staging study of endometrial carcinoma" for mutations in FGFR2. We will determine the frequency and spectrum of mutations and the relationship between mutations and outcome. Furthermore, we will determine how FGFR2 mutations are related to important clinical variables and other molecular abnormalities in endometrial cancers. These studies are an important first step in considering anti-FGFR2 treatments for endometrial cancer.